Smoking remains the leading, preventable cause of death in the U.S., yet surprisingly little is known about the causes of nicotine addiction. Chronic nicotine exposure results in behavioral and physiological changes that most likely arise from nicotine binding to neuronal nicotinic receptors (rxAChRs). These changes include chronic tolerance to the effects of nicotine in humans and laboratory animals, and changes in nAChR number and function. There appears to be a genetic component to nicotine tolerance in mice, and similarly, smoking appears to be influenced by genetics. One goal of the proposed set of experiments is to learn to what extent nAChR function is genetically influenced, using inbred mouse strains that differ with respect to the extent of tolerance development. Furthermore, little is known about genetic components of withdrawal from nicotine, and there exist vast differences in withdrawal symptoms in smokers. A mouse model of nicotine withdrawal will be developed in order to examine somatic and motivational components of withdrawal, and investigate any genetic contribution. Also largely unknown are the nAChR subtypes that regulate tolerance and withdrawal. A third goal is to examine the role of beta2 and alpha7 nAChR subunits using beta2 and alpha7 null mutant mice. A major beta2-containing nAChR subtype is the alpha4beta2 nAChR and as it, along with the alpha7 are the most abundant in brain, they will be examined.